title: The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes.
abstract: Tobacco smoke and air pollutants contain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and tobacco specific nitrosamines (TSNA), that are substrates of metabolizing enzymes generating reactive metabolites that can bind to DNA. Variation in the activity of these enzymes may modify the extent to which these metabolites can interact with DNA. We compared the levels of bulky DNA adducts in blood leukocytes from 93 volunteers living in Mexico City with the presence of 13 single nucleotide polymorphisms (SNPs) in genes related to PAH and TSNA metabolism (AhR rs2044853, CYP1A1 rs1048943, CYP1A1 rs1048943, CYP1A1 rs1799814, EPHX1 rs1051740, EPHX1 rs2234922, GSTM1 null, GSTT1 null and GSTP1 rs947894), DNA repair (XRCC1 rs25487, ERCC2 rs13181 and MGMT rs12917) and cell cycle (TP53 rs1042522). (32)P-postlabeling analysis was used to quantify bulky DNA adduct formation. Genotyping was performed using PCR-RFLP. The mean levels of bulky DNA adducts were 8.51±3.66 adducts/10(8) nucleotides (nt) in smokers and 8.38±3.59 adducts/10(8) nt in non-smokers, being the difference not statistically significant. Without taking into account the smoking status, GSTM1 null individuals had a marginally significant lower adduct levels compared with GSTM1 volunteers (p=0.0433) and individuals heterozygous for MGMT Leu/Phe had a higher level of bulky adducts than those who were homozygous wild type (p=0.0170). A multiple regression analysis model showed a significant association between the GSTM1 (deletion) and MGMT rs12917 (Phe/Phe) haplotype and the formation of DNA adducts in smokers (R(2)=0.2401, p=0.0215). The presence of these variants conferred a greater risk for higher adduct levels in this Mexican population.
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, Mexico City 04510, Mexico.
authors.forename: Edith
authors.initials: E
authors.lastname: Molina
authors.forename: Rebeca
authors.initials: R
authors.lastname: Pérez-Morales
authors.forename: Julieta
authors.initials: J
authors.lastname: Rubio
authors.forename: Pavel
authors.initials: P
authors.lastname: Petrosyan
authors.forename: Leticia Hernández
authors.initials: LH
authors.lastname: Cadena
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: María E
authors.initials: ME
authors.lastname: Gonsebatt
mesh_terms: D018736:DNA Adducts / Q000097:blood*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007962:Leukocytes / Q000737:chemistry*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018736:DNA Adducts; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D005982:Glutathione Transferase; D025521:Tumor Suppressor Proteins; C515491:MGMT protein, human
keywords: BER; BPDE; Benzo[a]pyrene-7,8-diol-9,10-epoxide; DNA double-strand breaks; DRR; DSB; ERCC2/XPD; GSTM1; Gene interaction ;(32)P-postlabeling; MGMT; NER; O(6)-methylguanine-DNA methyltransferase; PAH; Risk polymorphisms; SNP; X-ray repair cross complementation-1; XRCC1; base excision repair; direct reversal repair; excision repair cross complementing complementation group 2/xeroderma pigmentosum D; mEH; microsomal epoxide hydrolase; nt; nucleotide excision repair; nucleotides; polycyclic aromatic hydrocarbon; single nucleotide polymorphism